Spatial distributions of pericellular stiffness in natural extracellular matrices are dependent on cell-mediated proteolysis and contractility.

Bulk tissue stiffness has been correlated with regulation of cellular processes and conversely cells have been shown to remodel their pericellular tissue according to a complex feedback mechanism critical to development, homeostasis, and disease. However, bulk rheological methods mask the dynamics within a heterogeneous fibrous extracellular matrix (ECM) in the region proximal to a cell (pericellular region). Here, we use optical tweezers active microrheology (AMR) to probe the distribution of the complex material response function (α=α'+α″, in units of µm/nN) within a type I collagen ECM, a biomaterial commonly used in tissue engineering. We discovered cells both elastically and plastically deformed the pericellular material. α' is wildly heterogeneous, with 1/α' values spanning three orders of magnitude around a single cell. This was observed in gels having a cell-free 1/α' of approximately 0.5nN/µm. We also found that inhibition of cell contractility instantaneously softens the pericellular space and reduces stiffness heterogeneity, suggesting the system was strain hardened and not only plastically remodeled. The remaining regions of high stiffness suggest cellular remodeling of the surrounding matrix. To test this hypothesis, cells were incubated within the type I collagen gel for 24-h in a media containing a broad-spectrum matrix metalloproteinase (MMP) inhibitor. While pericellular material maintained stiffness asymmetry, stiffness magnitudes were reduced. Dual inhibition demonstrates that the combination of MMP activity and contractility is necessary to establish the pericellular stiffness landscape. This heterogeneity in stiffness suggests the distribution of pericellular stiffness, and not bulk stiffness alone, must be considered in the study of cell-ECM interactions and design of complex biomaterial scaffolds. STATEMENT OF SIGNIFICANCE: Collagen is a fibrous extracellular matrix (ECM) protein widely used to study cell-ECM interactions. Stiffness of ECM has been shown to instruct cells, which can in turn modify their ECM, as has been shown in the study of cancer and regenerative medicine. Here we measure the stiffness of the collagen microenvironment surrounding cells and quantitatively measure the dependence of pericellular stiffness on MMP activity and cytoskeletal contractility. Competent cell-mediated stiffening results in a wildly heterogeneous micromechanical topography, with values spanning orders of magnitude around a single cell. We speculate studies must consider this notable heterogeneity generated by cells when testing theories regarding the role of ECM mechanics in health and disease.

Improved regional ventricular function after successful surgical revascularization.

Left ventricular segments with reversible asynergy at rest demonstrate reversible myocardial perfusion defects on exercise thallium-201 scintigrams. To determine if improved perfusion eliminates asynergy at rest, 23 patients with angina (stable in 21, unstable in 2) were studied before and after coronary artery bypass surgery. All patients underwent exercise myocardial perfusion scintigraphy, contrast ventriculography and coronary arteriography before and after surgery. Selective graft angiography was performed during the postoperative catheterization to determine graft patency. Segmental ventricular function was quantitated by a regional fraction method. The scintigrams were divided into five regions and compared with the corresponding regions of the ventriculogram. Seventy-one of a possible 142 ventricular segments exhibited exercise-induced perfusion deficits. Preoperative regional ejection fraction was normal in 42 of these segments and abnormal in 29. Postoperatively, in 19 of the abnormal segments, function improved or normalized. All these segments had improved perfusion during exercise after surgery and were supplied by a patent bypass graft. Nine of the 10 segments in which abnormal wall motion persisted postoperatively continued to have exercise-induced perfusion deficits, and 9 of the 10 segments were supplied by an occluded or stenotic graft or one with poor run off. Of the 42 segments with normal wall motion preoperatively, 30 had improved perfusion after surgery and 35 maintained normal function. This study indicates that asynergy at rest is permanently reversed after coronary bypass surgery if improved myocardial perfusion can be documented. These findings are consistent with but do not prove the concept that reversible rest asynergy may reflect chronic ischemia or a prolonged effect from previous ischemic episodes.

Hemodynamic and clinical evaluation of piroximone, a new inotrope-vasodilator agent, in severe congestive heart failure.

To assess the potential utility of piroximone (MDL-19,205), an investigational inotrope-vasodilator agent, in severe heart failure, 15 patients with severe left ventricular failure refractory to conventional agents were enrolled in an acute hemodynamic study. After incremental intravenous dosing (mean total dose 1.8 +/- 0.4 mg/kg body weight), cardiac index increased (1.7 +/- 0.3 to 2.6 +/- 0.6 liters/min per m2; p less than 0.001) and left ventricular filling pressure decreased (25 +/- 7 to 19 +/- 7 mm Hg; p less than 0.001). Also decreasing significantly were right atrial pressure (13 +/- 6 to 7 +/- 5 mm Hg; p less than 0.005) and systemic vascular resistance (1,633 +/- 394 to 1,183 +/- 278 dynes.s.cm-5; p less than 0.001). Heart rate and mean arterial pressure did not change, whereas stroke work index increased significantly (13.3 +/- 4.3 to 21.6 +/- 7.3 g.m/m2; p less than 0.005). The increase in stroke work index with a concomitant decrease in left ventricular filling pressure indicates an improvement in systolic performance after treatment with piroximone. Similar responses were obtained after incremental doses of piroximone in oral solution. After oral doses of piroximone tablets, cardiac index also increased significantly (2.1 +/- 0.6 to 2.4 +/- 0.5 liters/min per m2; p less than 0.05), although this magnitude of increase was comparatively low. In a subgroup of 10 patients who underwent equilibrium gated radionuclide blood pool scintigraphy before and after intravenous piroximone, end-diastolic volume index tended to increase (106 +/- 42 to 132 +/- 60 ml/m2; p = 0.07), whereas left ventricular filling pressure decreased significantly (26 +/- 8 to 19 +/- 9 mm Hg; p less than 0.01).

Catheter-induced His bundle ablation in a patient with reentrant tachycardia associated with a nodoventricular tract.

A patient with refractory tachycardia associated with a nodoventricular tract in whom tachycardia was successfully controlled with catheter-induced ablation of the His bundle is reported. Tachycardia was always initiated by ventricular impulses that blocked retrogradely in the nodoventricular tract and conducted by way of the His-Purkinje system. The His bundle ablation was successfully accomplished by delivering two direct current countershocks of 400 J each in the region of the His bundle. Postablation, the patient manifested stable 1:1 anterograde conduction via the atrioventricular (AV) node-nodoventricular fiber over a wide range of heart rates (50 to 180 beats/min). A permanent pacemaker was not implanted at the patient's request. During 16 months of follow-up, the patient has had stable sinus rhythm with no sustained tachycardia. Brief asymptomatic episodes of ectopic atrial tachycardia have been recorded on ambulatory electrocardiographic monitoring. This case 1) demonstrates the potential role of ablation of the His bundle in patients with refractory tachycardia associated with a nodoventricular tract provided that the His bundle is a critical component in the initiation of the tachycardia or a part of the tachycardia circuit; 2) reveals stable 1:1 AV conduction over a nodoventricular tract; and 3) emphasizes the utility of the phase image technique for diagnosis of a Mahaim tract.

Interaction of "supplementary" scintigraphic indicators of ischemia and stress electrocardiography in the diagnosis of multivessel coronary disease.

Lung uptake, ventricular cavitary dilation and basal myocardial uptake represent abnormalities that have been associated with myocardial ischemia on stress thallium-201 images, but that are supplementary to the conventional assessment of perfusion distribution. These "supplementary" indicators of ischemia were related to the coronary distribution of perfusion abnormalities, the results of electrocardiographic stress testing and to the findings on coronary angiography in 73 patients. Forty patients had multivessel coronary disease; 19 of these had three vessel disease. Perfusion abnormalities were seen in 39 of these 40 patients but were indicative of multivessel coronary disease in only 28 and of three vessel disease in only 6. However, supplementary indicators were present in 33 of 40 patients with multivessel disease and in 15 of 19 with three vessel disease. Furthermore, they were seen in 16 of 22 patients with multivessel disease in whom conventional perfusion abnormalities underestimated the extent of disease, but in only 4 of 12 patients in whom the extent of disease was overestimated. The presence of either perfusion abnormalities in a multivessel distribution or supplementary indicators identified 38 (95%) of 40 patients with multivessel disease. A markedly positive electrocardiographic treadmill test was a less sensitive indicator of multivessel disease, appearing in only 15 of 40 patients. However, it was present in only 4 of 33 patients without multivessel coronary disease and was more specific for that diagnosis than were supplementary scintigraphic indicators (88 versus 67%, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Scintigraphic assessment of sympathetic innervation after transmural versus nontransmural myocardial infarction.

To evaluate the feasibility of detecting denervated myocardium in the infarcted canine heart, the distribution of sympathetic nerve endings using I-123 metaiodobenzylguanidine (MIBG) was compared with the distribution of perfusion using thallium-201, with the aid of color-coded computer functional map in 16 dogs. Twelve dogs underwent myocardial infarction by injection of vinyl latex into the left anterior descending coronary artery (transmural myocardial infarction, n = 6), or ligation of the left anterior descending coronary artery (nontransmural myocardial infarction, n = 6). Four dogs served as sham-operated controls. Image patterns were compared with tissue norepinephrine content and with histofluorescence microscopic findings in biopsy specimens. Hearts with transmural infarction showed zones of absent MIBG and thallium, indicating scar. Adjacent and distal regions showed reduced MIBG but normal thallium uptake, indicating viable but denervated myocardium. Denervation distal to infarction was confirmed by reduced norepinephrine content and absence of nerve fluorescence. Nontransmural myocardial infarction showed zones of wall thinning with decreased thallium uptake and a greater reduction or absence of MIBG localized to the region of the infarct, with minimal extension of denervation beyond the infarct. Norepinephrine content was significantly reduced in the infarct zone, and nerve fluorescence was absent. These findings suggest that 1) MIBG imaging can detect viable and perfused but denervated myocardium after infarction; and 2) as opposed to the distal denervation produced by transmural infarction, nontransmural infarction may lead to regional ischemic damage of sympathetic nerves, but may spare subepicardial nerve trunks that course through the region of infarction to provide a source of innervation to distal areas of myocardium.

Variability in coronary hemodynamics in response to ergonovine in patients with normal coronary arteries and atypical chest pain.

Because an increase in coronary vascular resistance in response to ergonovine maleate has been suggested as a possible diagnostic aid for variant angina, changes were evaluated in coronary hemodynamics and serial myocardial thallium-201 perfusion scans in 15 patients without angina and with normal coronary arteries in response to ergonovine (0.05, 0.10 and 0.20 mg intravenously). For the group, heart rate-blood pressure product increased significantly (p less than 0.001) without any change in coronary sinus flow, coronary vascular resistance, myocardial oxygen extraction, arterial-coronary sinus oxygen difference and lactate extraction. In 7 of 15 patients, however, coronary vascular resistance increased (mean 39%, range 11 to 75%, probability [p] less than 0.001), and coronary sinus flow decreased (14%, p less than 0.001), despite an increase in heart rate-blood pressure product (36%, p less than 0.02). No electrocardiographic, metabolic or thallium-201 scan abnormalities occurred. Therefore, significant increases in coronary vascular resistance in response to ergonovine may occur in patients with normal coronary arteries and atypical chest pain.

Nuclear magnetic resonance imaging-guided phosphorus-31 spectroscopy of the human heart.

Phosphorus-31 nuclear magnetic resonance spectroscopy can determine the status of high energy phosphates in vivo. However, its application to human cardiac studies requires precise spatial localization without significant contamination from other tissues. Using image-selected in-vivo spectroscopy (ISIS), a technique that allows three-dimensional localization of the volume of interest, 12 subjects were studied to determine the feasibility and reproducibility of phosphorus-31 spectroscopy of the human heart. Nuclear magnetic resonance imaging was performed using a commercial 1.5 tesla system to define the volume of interest. Phosphorus-31 spectra were obtained from the septum and anteroapical region of the left ventricle in 10 studies. Relative peak heights and areas were determined for high energy phosphates. The mean phosphocreatine to adenosine triphosphate ratio was 1.33 +/- 0.19 by height analysis and 1.23 +/- 0.27 by area analysis. Duplicate measurements in four subjects showed a reproducibility of less than or equal to 10% in three of the subjects. All spectra showed significant signal contribution from the 2,3 diphosphoglycerate in chamber red cells without evidence of skeletal muscle contamination. These results demonstrate the feasibility of image-guided phosphorus-31 spectroscopy for human cardiac studies and indicate the potential of this technique to study metabolic disturbances in human myocardial disease.

The scintigraphic characteristics of ventricular pre-excitation through Mahaim fibers with the use of phase analysis.

The phase image pattern of blood pool scintigrams was blindly assessed in 11 patients exhibiting conduction through Mahaim pathways, including 6 nodoventricular and 5 fasciculoventricular. These patterns were compared with the phase image findings in normal subjects, patients with left and right bundle branch block in the absence of pre-excitation and patients with pre-excitation through atrioventricular (AV) connections. In all patients with a Mahaim pathway, the site of earliest phase angle was septal or paraseptal. Phase progression was asymmetric and the pre-excited ventricle demonstrated the earliest mean ventricular phase angle in 10 of 11 patients. This pattern, and the associated ventricular phase difference, appeared to vary from that in normal subjects and in those with a septal AV connection, in whom phase progression is generally symmetric. Scintigraphic phase analysis provided localizing information and presented patterns consistent with Mahaim pathways. Although not able to differentiate among Mahaim pathway subtypes, these phase patterns differed from those in normal subjects, those with right and left lateral free wall pathways and most patients with a septal AV pathway. However, the phase pattern of patients with a Mahaim pathway may not differ from that of patients with a septal AV connection displaying an asymmetric pattern of phase progression, or those with left and right bundle branch block in the absence of pre-excitation. Objective, yet imperfect phase measurements supported these differences. Such image findings may complement the often complex electrophysiologic evaluation of patients presenting with pre-excitation.

Phase image characterization of localized and generalized left ventricular contraction abnormalities.

To evaluate their phase image characteristics, 61 patients with varying left ventricular contraction abnormalities were studied. In 16 normal patients, the left ventricular phase image revealed a homogeneous pattern, a narrow bell-shaped histogram and an orderly spatial progression of phase angle (phi). In 16 patients with segmental abnormalities, the left ventricular phase image showed a region of uniformly delayed phase angle corresponding to the site of segmental abnormality, a discrete secondary histogram peak and a discontinuous, but orderly, spatial progression of phase angle. The mean phase angle (phi) (23.6 +/- 15.7 degrees) and its standard deviation (17.6 +/- 7.2 degrees) differed from the normal group (7.6 +/- 11.1 degrees, p less than 0.002 and 8.9 +/- 2.8 degrees, p less than 0.001). The percent of end-diastolic volume involved in the segmental abnormality, calculated using phase data in 13 of these and in 11 additional patients with a left ventricular aneurysm on ventriculography, correlated well with the percent akinetic segment on scintigraphic (r = 0.78) and angiographic (r = 0.84) study. In 18 patients with generalized abnormalities, the left ventricular phase image revealed multiple regions of inhomogeneous phase angle, a grossly irregular histogram and a disorderly spatial progression of phase angle. The mean phase angle (56.4 +/- 23.9 degrees) and standard deviation (27.3 +/- 7.1 degrees) differed from values in the normal group and from patients with segmental contraction abnormalities (both p less than 0.001). The mean phase angle and its standard deviation in scattered regions with abnormally prolonged phase angle differed significantly from abnormal regions in patients with segmental abnormalities (both p less than 0.001). These patterns of left ventricular phase angle demonstrate characteristics that may help differentiate between ventricles with segmental and generalized contraction abnormalities. Their relation to underlying pathophysiology and potential clinical implications should be considered.

Phase image evaluation of patients with ventricular pre-excitation syndromes.

To localize bypass pathways, left and right ventricular regions were analyzed at rest by phase image analysis in 18 patients with ventricular pre-excitation syndromes. These were compared with image findings in 18 normal subjects. In each of 17 patients with pre-excitation, the site localized on electrophysiologic study correlated closely with the region of earliest ventricular phase angle. This site could be objectively separated from that in normal subjects in each of eight patients with an active left-sided pathway and in both patients with a right-sided pathway. Those with a septal pathway revealed earliest septal phase angle, but could not be separated from normal subjects. In the eight patients with an active left bypass tract, the onset, upstroke and peak of the left ventricular phase histogram preceded those of the right ventricular histogram. Those with a left-sided pathway demonstrated a mean left ventricular phase angle, a difference between mean left and mean right ventricular phase angle and a difference between earliest left and right ventricular phase angles which was significantly less than that in normal subjects (p less than 0.05). These variables presented characteristic converse changes in those with a right-sided pathway. Sequential phase changes in 10 studies suggested "fusion" of normal septal with lateral bypass fronts. Electrocardiographic and electrophysiologic localization of the bypass pathway agreed in only 8 of 14 patients with a recognized delta wave. The phase image represents a new, noninvasive method of evaluating ventricular pre-excitation. The method may provide useful information complementary to that of electrocardiographic and electrophysiologic analysis.

Volume loading improves low cardiac output in experimental right ventricular infarction.

To evaluate the effect of volume loading in the low output state associated with right ventricular infarction, isolated right ventricular infarction was produced in seven dogs with the pericardium intact. Volume loading and pericardiotomy were then sequentially performed. After the production of right ventricular infarction, right ventricular systolic pressure decreased by 25%, aortic pressure by 36% and cardiac output by 32%. Right ventricular ejection fraction decreased by 57%, but left ventricular ejection fraction did not change significantly. Left ventricular transmural pressure and diastolic size decreased, and right ventricular diastolic size increased. Intrapericardial pressure increased and equalization of diastolic pressures was noted. Volume loading resulted in increased right ventricular systolic pressure and stroke work, increased aortic pressure and cardiac output and increased transmural pressure and diastolic size in both ventricles. Pericardiotomy resulted in further increases in right and left ventricular filling, stroke work and cardiac output, as well as resolution of equalized diastolic pressures. These results indicate that cardiac output in experimental right ventricular infarction increases with volume loading, which enhances left ventricular preload by augmenting right ventricular output. Elevated intrapericardial pressure affects filling of both ventricles and may play a role in the pathophysiology of low cardiac output in right ventricular infarction.

Assessment of cardiac anatomy using nuclear magnetic resonance imaging.

Nuclear magnetic resonance imaging has emerged in the past few years as a completely noninvasive method for medical imaging of internal organs. Because of the loss of signal intensity by motional nuclei (hydrogen) using most proton imaging techniques, flowing blood within the cardiovascular system generates little or no signal and consequently there is high natural contrast between blood and the walls of blood vessels or cardiac chambers. However, motion during imaging also complicates cardiac imaging because signal is lost from the nuclei in the moving cardiac structures. Consequently electrocardiographic gating of data acquisition is required for nuclear magnetic resonance imaging of the heart. Distinct advantages of nuclear magnetic resonance imaging in relation to other imaging modalities are good contrast between soft tissues and the capability for characterization of specific tissues by estimation of magnetic relaxation times. Early in vitro studies measuring relaxation times of myocardial tissue samples of excised hearts indicate that nuclear magnetic resonance imaging will be capable of discriminating infarcted from normal myocardium. Recent studies using electrocardiographically gated nuclear magnetic resonance imaging of dogs with acute infarction showed the infarct as a region of high intensity on spin-echo images. Initial clinical experience with electrocardiographically gated nuclear magnetic resonance imaging (0.35 tesla) in patients has clearly defined internal cardiac anatomy without the use of contrast media. This technique has demonstrated the consequence of previous myocardial infarction such as regional wall thinning, aneurysm, thrombus and contractile dysfunction, a number of pericardial abnormalities and the morphology of hypertrophic and congestive cardiomyopathies.

Comparison of the findings on preoperative dipyridamole perfusion scintigraphy and intraoperative transesophageal echocardiography: implications regarding the identification of myocardium at ischemic risk.

The evidence of myocardium at potential ischemic risk on preoperative dipyridamole perfusion scintigraphy was compared with that of manifest ischemia on intraoperative transesophageal echocardiography in 26 patients at high risk of a coronary event undergoing noncardiac surgery. The clinical outcome was also assessed. Induced intraoperative wall motion abnormalities were more common in patients and myocardial segments with, than in those without, a preoperative reversible perfusion defect (both p less than 0.05). Conversely, a preoperative reversible perfusion defect was more common in patients and segments with, than in those without, a new intraoperative wall motion abnormality (both p less than 0.05). Six patients, five with a reversible scintigraphic defect but only three with a new wall motion abnormality, had a hard perioperative ischemic event. Events occurred more often among patients with, than in those without, a reversible perioperative scintigraphic defect (5 [33%] of 15 vs. 1 [9%] of 11) but this difference did not reach significance (p = 0.14), probably owing to the sample size. Intraoperative wall motion abnormalities were all reversible and did not differentiate between risk groups; these findings were possibly influenced by treatment. These preliminary data support the known relation between reversible scintigraphic defects and perioperative events and identify another manifestation of ischemic risk in the relation between reversible scintigraphic defects and induced intraoperative wall motion abnormalities. The value of intraoperative echocardiography in identifying ischemia and guiding therapy in patients with a reversible scintigraphic abnormality should be further assessed.

Quantitation of regional myocardial function by cine computed tomography: pharmacologic changes in wall thickness.

To determine the capability of high speed computed transmission tomography to quantitate regional wall thickening dynamics over a wide range of physiologic states, left ventricular wall thickening was studied in nine anesthetized mongrel dogs in the control state and during separate infusions of dobutamine (10 micrograms/kg per min) and phenylephrine (25 micrograms/kg per min). After an intravenous bolus of contrast medium the heart was imaged from base to apex with serial transverse images in eight short-axis cine computed tomographic planes. In each dog during each experimental condition, 50 ms scans spanning the cardiac cycle were acquired at each anatomic level. Left ventricular epicardial and endocardial boundaries were identified on end-diastolic and end-systolic images at the equatorial left ventricular planes by an objective threshold contour method validated in a series of experiments performed on ex vivo anatomic specimens. End-diastolic and end-systolic frames were automatically realigned by superposition of epicardial centers of gravity and then rotated using a cross correlation function. The left ventricular wall thickness was measured manually at 16 points around the circumference by two independent observers. For the group of dogs the average percent wall thickening was 40.5 +/- 28.2% and varied among segments from 18 to 70% in the control state. After dobutamine was administered, significant increases in heart rate and cardiac output (p less than or equal to 0.01) were accompanied by an increase in the average wall thickening (73.6 +/- 51.2%; p less than or equal to 0.001) in the left ventricle; the average wall thickening among segments ranged from 46 to 97%. After phenylephrine administration, significant increases in mean blood pressure and cardiac output (p less than or equal to 0.01) were noted along with a significant increase in average left ventricular wall thickening (60.3 +/- 52.5%; p less than or equal to 0.001). Despite an overall increase in the percent wall thickening, no statistically significant changes in segmental contraction pattern between control and drug intervention states were observed. The wall thickness measurements were highly reproducible between the two independent readers (reliability coefficient = 0.99). Cine computed tomography-derived measurements can potentially be used for quantitative assessment of left ventricular wall thickening dynamics of a single heartbeat during acute interventions, such as the administration of drugs.

Ventricular contraction abnormalities in dilated cardiomyopathy: effect of biventricular pacing to correct interventricular dyssynchrony.

OBJECTIVE: To measure ventricular contractile synchrony in patients with dilated cardiomyopathy (DCM) and to evaluate the effects of biventricular pacing on contractile synchrony and ejection fraction. BACKGROUND: Dilated cardiomyopathy is characterized by abnormal ventricular activation and contraction. Biventricular pacing may promote a more coordinated ventricular contraction pattern in these patients. We hypothesized that biventricular pacing would improve synchrony of right ventricular and left ventricular (RV/LV) contraction, resulting in improved ventricular ejection fraction. METHODS: Thirteen patients with DCM and intraventricular conduction delay underwent multiple gated equilibrium blood pool scintigraphy. Phase image analysis was applied to the scintigraphic data and mean phase angles computed for the RV and LV. Phase measures of interventricular (RV/LV) synchrony were computed in sinus rhythm and during atrial sensed biventricular pacing (BiV). RESULTS: The degree of interventricular dyssynchrony present in normal sinus rhythm correlated with LV ejection fraction (r = -0.69, p < 0.01). During BiV, interventricular contractile synchrony improved overall from 27.5 +/- 23.1 degrees to 14.1 +/- 13 degrees (p = 0.01). The degree of interventricular dyssynchrony present in sinus rhythm correlated with the magnitude of improvement in synchrony during BiV (r = 0.83, p < 0.001). Left ventricular ejection fraction increased in all thirteen patients during BiV, from 17.2 +/- 7.9% to 22.5 +/- 8.3% (p < 0.0001) and correlated significantly with improvement in RV/LV synchrony during BiV (r = 0.86, p < 0.001). CONCLUSIONS: Dilated cardiomyopathy with intraventricular conduction delay is associated with significant interventricular dyssynchrony. Improvements in interventricular synchrony during biventricular pacing correlate with acute improvements in LV ejection fraction.

Effects of long-term right ventricular apical pacing on left ventricular perfusion, innervation, function and histology.

OBJECTIVES: The purpose of this study was to better understand the effects of long-term right ventricular pacing on left ventricular perfusion, innervation, function and histology. BACKGROUND: Long-term right ventricular apical pacing is associated with increased congestive heart failure and mortality compared with atrial pacing. The exact mechanism for these changes is unknown. In this study, left ventricular perfusion, sympathetic innervation, function and histologic appearance after long-term pacing were studied in dogs in an attempt to see whether basic changes might be present that might ultimately be associated with the adverse clinical outcome. METHODS: A total of 24 dogs were studied. Sixteen underwent radiofrequency ablation of the atrioventricular (AV) junction to produce complete AV block. Seven of these underwent long-term pacing from the right ventricular apex (ventricular paced group), and nine had atrial and right ventricular apical pacing with AV synchrony (dual-chamber paced group). A control group of eight dogs had sham ablations with normal AV conduction. These dogs had atrial pacing only. Regional perfusion and sympathetic innervation were studied in all dogs by imaging with thallium-201 and [I123]metaiodobenzylguanidine, respectively. The degree of innervation was also determined by assay of tissue norepinephrine levels. Left ventricular function was assessed by radionuclide ventriculography. Cardiac histology was studied with both light and electron microscopy. RESULTS: Mismatching of perfusion and innervation in the ventricular paced group was noted, with perfusion abnormalities of both the septum and free wall. Regional [I123]metaiodobenzylguanidine distribution was homogeneous. Tissue norepinephrine levels were elevated in both the ventricular and dual-chamber paced groups compared with the control group. No light or electron microscopic findings were noted in any groups. In the dual-chamber paced group, diastolic dysfunction was noted, with normal systolic function. CONCLUSIONS: Ventricular pacing resulted in regional changes in tissue perfusion and heterogeneity between perfusion and sympathetic innervation. Both ventricular and dual-chamber pacing were associated with an increase in tissue catecholamine activity. The abnormal activation of the ventricles via right ventricular apical pacing may result in multiple abnormalities of cardiac function, which may ultimately affect clinical outcome.

Diagnostic test use in different practice settings. A controlled comparison.

Health maintenance organizations (HMOs) have lower than average medical care costs, but the reasons remain controversial. The diagnostic practices of cardiologists from an HMO, a university, and a community were therefore surveyed. First, cardiologists defined indications for coronary bypass surgery and then evaluated randomly selected case summaries of patients with chest pain. After review, the cardiologist rated the need for an exercise thallium scintiscan and for a coronary angiogram in each case. Community cardiologists had the broadest indications for bypass surgery. The HMO cardiologists chose thallium scintigraphy significantly less often than the other two types of cardiologists did. The HMO and university cardiologists both rated the need for coronary angiography significantly lower than did community cardiologists. Physicians in different practice settings therefore recommend costly diagnostic and therapeutic methods differently, even for identical patients.

Acute and chronic effects of transient myocardial ischemia on sympathetic nerve activity, density, and norepinephrine content.

OBJECTIVES: The sympathetic nervous system has profound influences on myocardial function, particularly during ischemia. There is controversy, however, as to whether myocardial ischemia results in damage to myocardial sympathetic nerves coursing through the ischemic territory. To further evaluate these issues, we assessed the acute and chronic effects of transient myocardial ischemia on sympathetic nerve function and morphology. METHODS: A total of 20 dogs were studied. For acute studies (n = 9), we performed serial dynamic imaging of I-123 metaiodobenzylguanidine (MIBG) washout during coronary occlusion and reperfusion, and assessed residual myocardial perfusion with thallium-201. For chronic studies (n = 11), we assessed sympathetic innervation and perfusion 11 days following a transient intracoronary balloon occlusion. Imaging results were correlated with electrocardiographic responses, histology, and tissue norepinephrine (NE). RESULTS: In the acute studies, regional MIBG washout increased more than 2-fold in the ischemic territory compared to the control region during coronary occlusion (14.2 +/- 2.3 vs. 5.9 +/- 1.2%, P < 0.01). Tissue NE was reduced in the ischemic territory compared to the non-ischemic territory (335 +/- 162 vs. 751 +/- 190 ng/g, P < 0.01). Myocardial perfusion was normal. In the chronic studies, 9/11 dogs showed ischemic ECG changes during balloon occlusion, and developed ventricular arrhythmias. On follow-up imaging, 5/11 dogs showed reduced MIBG uptake relative to thallium, in viable myocardium overlying necrotic subendocardium, reduced NE (226 +/- 77 vs. 733 +/- 82 ng/g in control regions, P < 0.01), decreased nerve density, and a larger extent of denervation than scar (25.5 +/- 3.7 vs. 8.2 +/- 2.7%, P < 0.02). Six of 11 dogs showed normal innervation patterns. CONCLUSIONS: These studies suggest that the sympathetic nerves are acutely affected in regions of myocardial ischemia as detected by enhanced regional washout of MIBG. In addition, chronic sympathetic nerve denervation can occur in the absence of transmural myocardial necrosis; however, the occurrence of transient ischemia does not predict the development of chronic denervation. The severity of ischemia, as evidenced by the extent of the related necrosis, does appear to predict chronic denervation. The severity of ischemia, as evidenced by the extent of the related necrosis, does appear to predict chronic denervation. The mechanisms leading to chronic denervation of sympathetic nerves in the absence of transmural infarction remain to be defined.

Substrate regulation of the nucleotide pool during regional ischaemia and reperfusion in an isolated rat heart preparation: a phosphorus-31 magnetic resonance spectroscopy analysis.

Isolated rat heart preparations were studied to characterise the alterations in high energy phosphates that occur during reversible regional ischaemia and to determine whether pyruvate, as the sole exogenous energy substrate, would attenuate the ischaemia induced depletion of the nucleotide pool when compared with glucose. Using phosphorus-31 magnetic resonance spectroscopy baseline concentrations of adenosine triphosphate, phosphocreatine, inorganic phosphate, and intracellular pH were compared with values during 30 min of left coronary artery occlusion followed by 30 min of reperfusion. These variables were related to changes in developed pressure, coronary flow, and oxygen consumption. In addition, the total nucleotide pool was evaluated by biochemical analysis of myocardial tissue extracts and coronary effluent. The ischaemic region was characterised by a dye staining technique and cross sectional echocardiographic measurements of regional myocardial wall thinning. In both glucose and pyruvate perfused groups, coronary flow and oxygen consumption decreased to 50-60% of control within 1 min of ischaemia and returned to baseline values with reflow. Developed pressure decreased to 50(9) and 74(8)% (mean(SEM] of control after 30 min of ischaemia in glucose and pyruvate perfused groups respectively. Reperfusion resulted in complete recovery of developed pressure in hearts perfused with pyruvate but not in the glucose group. Glucose perfused hearts had a greater decrease in intracellular pH during ischaemia (7.07(0.01) to 6.36(0.1] than pyruvate perfused hearts (7.06(0.02) to 6.83(0.04]. Reperfusion resulted in a rapid return to baseline intracellular pH in both groups. During ischaemia, adenosine triphosphate values decreased to a greater degree in glucose than in pyruvate perfused hearts (57(4) and 79(5)% of baseline respectively). Thirty minutes of reperfusion did not significantly improve adenosine triphosphate concentrations in either group. Phosphocreatine concentrations decreased to 52(7) and 75(6)% of baseline in glucose and pyruvate perfused groups respectively after the ischaemic period. Reperfusion resulted in normalisation of phosphocreatine values in the pyruvate but not in the glucose perfused group. Biochemical analysis of myocardial tissue extracts confirmed the spectroscopy data and showed that pyruvate inhibits the efflux of adenine nucleotide derivatives. Tissue concentrations of adenosine monophosphate were three times greater and adenosine 50% less after 30 min of ischaemia in the pyruvate perfused group.(ABSTRACT TRUNCATED AT 400 WORDS)